Cerebellum Gene Expression Changes With Chronic Ethanol

描述(由申请人提供)：慢性乙醇自我给药对大脑中整体基因表达的影响尚未得到广泛的表征。大多数检测大脑基因表达的研究都使用了啮齿动物模型、培养中的神经细胞或存档的人类尸检样本中的组织。虽然这些研究提供了丰富的信息，但这些模型系统的使用都有局限性。目前的研究建议从已知受慢性酒精摄入影响的大脑区域--小脑开始，对相关大脑区域的酒精敏感基因表达进行系统分析。尽管小脑参与与运动相关的行为是有充分证据的，但人们对了解小脑在酒精中毒认知变化中的作用越来越感兴趣。为了研究这个问题，这项研究将使用维克森林大学开发的一种非常独特和强大的非人类灵长类动物慢性乙醇自我给药模型。这些实验将用食蟹猴的脑组织进行，这些猴子连续18个月长期服用酒精(高达4.0g/kg/天)。使用该模型研究大脑基因表达有三方面的优势：(1)非人类灵长类动物在生理、遗传学和消费方面与人类非常相似，这使其成为一个非常相关的模型；(2)这些动物的整个(慢性)饮酒史已知；(3)可以评估全基因组基因表达的工具(高密度基因阵列)的可用性提供了实现前所未有的基因表达分析水平的可能性。由受试者内部设计(检查每只动物小脑的三个不同区域)以及组间设计(长期饮酒和酗酒之间的比较；男性和女性之间的比较)产生的基因表达数据将提供重要的新信息。确定非人类灵长类动物大脑中慢性乙醇自我给药引起的神经病理的分子基础应该与更好地理解人类酒精中毒有直接关系。

DESCRIPTION (provided by applicant): The effects of chronic ethanol self-administration on global gene expression in the brain have not been extensively characterized. The majority of studies to examine brain gene expression have used rodent models, neuronal cells in culture, or tissue from archived human autopsy samples. While these studies have provided a wealth of information, the use of each of these model systems has limitations. The present study proposes to initiate a systematic analysis of ethanol-sensitive gene expression in relevant brain regions by starting with a brain region known to be affected by chronic ethanol consumption - the cerebellum. Although cerebellar involvement in movement related behaviors is well documented, there is a growing interest understanding the role of the cerebellum in the cognitive changes that occur in alcoholism. To investigate this question, this study will use a very unique and robust nonhuman primate model of chronic ethanol self administration developed at Wake Forest University. These experiments will be conducted with brain tissue from cynomolgus monkeys who have self-administered ethanol for 18 consecutive months at chronic levels (up to 4.0 g/kg/day). The advantages of using this model to investigate brain gene expression are threefold: (1) the close similarity of non-human primate to humans in terms of physiology, genetics, and consumption render it a very relevant model; (2) the entire (chronic) drinking history for these animals is known and; (3) the availability of tools (high density gene arrays) that permit the evaluation of whole-genome gene expression provide the possibility to achieve a level of gene expression analysis never before possible. The gene expression data generated from a within-subject design (examining three separate regions of the cerebellum in each animal), as well as a between-group design (comparison between chronic alcohol and alcoholna'fve; comparison between males and females) will provide significant new information. Identifying the molecular basis of neuropathology in the nonhuman primate brain resulting from chronic ethanol self-administration should have direct relevance to better understanding human alcoholism.